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Page 1 Biorphen 0.1 mg/ml 1.3.1 Summary of Product Characteristics (SmPC)

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Biorphen 0.1 mg/ml, solution for injection/infusion Kommentiert [VR1]: Modified according to Day 30 Comments from the CMS the FI. Other relevant paragraphs have been modified accordingly . 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1ml of solution for injection/infusion contains 0.1 mg of hydrochloride corresponding to 0.08 mg of phenylephrine. Kommentiert [VR2]: According to Day 30 Comments from the CMS FI, 1 ampoule of 5 ml contains 0.5 mg of phenylephrine hydrochloride corresponding to 0.4 mg of Day 30 Comments from the CMS SE Kommentiert [VR3R2]: Applicant’s reply to NL and phenylephrine. SEcomment VAR DE/H/4407/001-002/008: already modified at day 60 of the RUP procedure Excipients with known effect: Kommentiert [VR4]: Comment from Slovenia: Latest Q RD 1 ampoule of 5 ml contains 0.77 mmol (or 17.7 mg) sodium. should be followed: For the full list of excipients, see section 6.1. Excipient(s) with known effect Kommentiert [VR5R4]: Modified accordingly

3. PHARMACEUTICAL FORM Solution for injection/infusion. A clear colourless solution free from visible particles. Kommentiert [PC6]: Modified according to Day 30 Comments from the CMS the RO and according to section 3.2.P.5.1 pH 3.0-5.0. Specification Osmolarity: 270 to 300 mOsm/l.

4. CLINICAL PARTICULARS 4.1 Therapeutic indications Biorphen is indicated in adults for treatment of during spinal, epidural or general Kommentiert [VR7]: Modified according to Day 30 Comments from the CMS the SI anaesthesia. Kommentiert [VR8]: Modified according to Day 30 Comments from the CMS the NL

4.34.2 Posology and method of administration

Route of Administration: Formatiert: Schriftart: Fett, Schriftfarbe: Automatisch, Englisch (Großbritannien), Rechtschreibung und Grammatik Biorphen 0.1 mg/ml, solution for infusion, for slow intravenous injection or intravenous infusion. nicht prüfen Biorphen 0.1 mg/ml, solution for infusion, should only be administered by healthcare professionals with appropriate training and relevant experience.Posology: Adults Intravenous bolus injection:

1 Page 2 Biorphen 0.1 mg/ml 1.3.1 Summary of Product Characteristics (SmPC)

The usual dose is 50 µg phenylephrine, which can be repeated for until the desired effect is achieved. In severe hypotension, doses may be increased, without but should not exceed 100 µg per bolus exceeding 100 µg in a bolus.

Continuous infusion:

Initial dose is 25 to 50 µg/min phenylephrine, up to 180 µg/min. The doses may be increased or Kommentiert [VR9]: Applicants reply to Day 30 Comments from the CMS Sweden decreased to maintain systolic blood pressure near the normal value. Doses between 25 and 100 µg/min The maximum dose of 180 µg/min is in line with information reported in the leaflet of the reference product Phenylephrine has been deemedare usually effective. Injection BP 10 mg/ml’ (rev. date Nov. 2018) The applicant would like to maintain the maximum dose of 180 µg/min as additional safety measure in order to avoid administration of excessive doses which could lead to overdose episodes and would like to maintain dosage indications in line with those reported in the SmPC of the Patients with renal impairment reference product.

Lower doses of Biorphen may be required in patients with renal impairment. Kommentiert [VR10R9]: Applicant’s reply to RMS’s PVAR DE/H/4407/001-002/008: the explanation has already been included Patients with hepatic impairment: in the Applicant reply at Day 60 Please refer to comment above. Higher doses of Biorphen may be needed in patients with liver cirrhosis. Kommentiert [VR11]: Applicant’s reply to DE updated PVAR: deleted accordingly Elderly patients: Kommentiert [VR12]: Applicant’s reply to updated PVAR: Treatment of the elderly should be made with caution. dosage section modified accordingly Paediatric population: The safety and efficacy of phenylephrine in children have not been established. No data are available.

Method of Administration: Kommentiert [VR13]: Modified according to Day 30 Comments from the CMS SI Biorphen 0.1 mg/ml, solution for injection/infusion, for slow intravenous injection or intravenous infusion. Biorphen 0.1 mg/ml, solution for injection/infusion, should only be administered by healthcare professionals with appropriate training and relevant experience.

4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Phenylephrine should not be given to patients with severe hypertension or peripheral vascular disease. This can lead to ischaemia with a risk of gangrene or vascular thrombosis.

In combination with indirectly acting sympathomimetic agents: risk of and / or hypertensive crisis (see section 4.5).

In combination with alpha-sympathomimetic agents (oral and / or nasal use): risk of vasoconstriction and / or hypertensive crisis (see section 4.5). Kommentiert [VR14]: Applicant’s reply to RMS 2nd updated FVAR: modified accordingly In combination with indirectly acting sympathomimetic agents (, methylphenidate, ): risk of vasoconstriction and / or hypertensive crisis.

2 Page 3 Biorphen 0.1 mg/ml 1.3.1 Summary of Product Characteristics (SmPC)

In combination with alpha-sympathomimetic agents (oral and / or nasal use) (, , , , , , , ): risk of vasoconstriction and / or hypertensive crisis. Kommentiert [VR15]: Applicant’s reply to NL comment VAR DE/H/4407/001-002/008: modified accordingly In combination with non-selective monoamine oxidase inhibitors (MAOs) (or within 2 weeks of their withdrawal) due to risk of paroxysmal hypertension and possibly fatal hyperthermia (see section 4.5).

Biorphen should not be given to patients with severe hyperthyroidism.

4.4 Special warnings and precautions for use Arterial blood pressure should be monitored during treatment. Biorphen should be given with caution to patients with:

• diabetes, • arterial hypertension, • aneurysma, • uncontrolled hyperthyroidism, • coronary heart disease and chronic heart disease, • bradycardia, • partial heart block, • tachycardia, • arrhythmias, • angina pectoris (phenylephrine can precipitate or exacerbate angina in patients with coronary artery disease and history of angina), • non-severe peripheral vascular insufficiency, • closed angle glaucoma.

Biorphen may induce a decrease in cardiac output. Therefore, it should be administered with extreme caution in patients with atherosclerosis in the elderly and in patients with impaired cerebral or coronary circulation. In patients with reduced cardiac output or coronary vascular disease, vital organ functions should be closely monitored and dose reduction should be considered when systemic blood pressure is near the lower end of the target range. Kommentiert [VR16]: According to Day 30 Comments from the CMS SE, the Applicant would like to shift the sentence and modify it accordingly . In patients with severe heart failure or cardiogenic , Biorphen may cause a worsening of heart failure as a result of the induced vasoconstriction (increased afterload).

Patients with medical conditions such as decreased cardiac output or peripheral coronary artery disease should have frequent monitoring of vital body functions and lower systemic blood pressure boundary should be considered as a criterion for dose reduction or discontinuation of Biorphen.

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Particular attention should be paid to phenylephrine injection to avoid extravasation, since this may cause tissue necrosis.

Lower doses may be required in patients with renal impairment. Higher doses may be required in patients with liver cirrhosis.

The administration of this drug simultaneously with the following medicines is not recommended because of the risk of vasoconstriction and / or hypertensive crisis associated with its indirect sympathomimetic effect (see section 4.5): • dopaminergic ergot alkaloids (, carbergoline, or ) or vasoconstrictors (, , or , )

• in combination with linezolid

This medicinal product contains 3.54 mg sodium per ml, equivalent to 0.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult. This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium-free’. Kommentiert [PC17]: According to Day 55 Comment from the CMS SI. 4.5 Interaction with other medicinal products and other forms of interaction Combinations that are contraindicated (see section 4.3) - Non-selective monoamine oxidase inhibitors (MAOIs) (iproniazid, nialamide): risk of paroxysmal hypertension, hyperthermia possibly fatal. Due to the long duration of action of MAOIs, this interaction is still possible 15 days after discontinuation of the MAOIs. - Indirect sympathomimetics agents (ephedrine, methylphenidate, pseudoephedrine): risk of vasoconstriction and / or hypertensive crisis. - Alpha sympathomimetic agents (oral and/or nasal use) (etilefrine, midodrine, naphazoline, oxymetazoline, synephrine, tetryzoline, tuaminoheptane, tymazoline): risk of vasoconstriction and / or hypertensive crisis.

Combinations not recommended (see section 4.4) - Dopaminergic ergot alkaloids (bromocriptine, , lisuride and pergolide): risk of vasoconstriction and/or hypertensive crisis. - Vasoconstrictor ergot alkaloids (dihydroergotamine, ergotamine, methylergometrine, methysergide): risk of vasoconstriction and/or hypertensive crisis. - Linezolid: risk of vasoconstriction and/or hypertensive crisis. - Tricyclic (, , ): risk of paroxysmal hypertension with possibility of arrhythmias (inhibition of or noradrenaline entry in sympathetic fibers). - Noradrenergic-serotoninergic antidepressants (minalcipram, venlafaxine): risk of paroxysmal hypertension with possibility of arrhythmias (inhibition of adrenaline or noradrenaline entry in sympathetic fibers).

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- Selective type A monoamine oxidase inhibitors (MAOs) (moclobemide, toloxatan): risk of vasoconstriction and/or hypertensive crisis. - and related products: substantial increase in blood pressure (hyperreactivity linked to the reduction in sympathetic tone and /or to the inhibition of adrenaline or noradrenaline entry in sympathetic fibers). If the combination cannot be avoided, use with caution lower doses of sympathomimetic agents. - Cardiac glycosides, : increased risk of arrhythmias. - Halogenated volatile anaesthetics (desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane): risk of perioperative hypertensive crisis and arrhythmia. -

Combinations requiring caution: Oxytocic agents: The effect of presso-active sympathomimetic amines is potentiated. Thus , some oxytocic agents may cause severe persistent hypertension and strokes can occur during post-partum period.

4.6 Fertility, pregnancy and lactation Fertility There are no data available regarding fertility after exposure to phenylephrine (see section 5.3). Pregnancy The safety of phenylephrine during pregnancy has not been established. Animal studies are insufficient with respect to effects on pregnancy, embryonal / fetal development, parturition or postnatal development. The potential risk for humans is unknown. Phenylephrine should not be used during pregnancy unless clearly necessary.

Breast-feeding Small amounts of phenylephrine are excreted in human milk. The administration of vasoconstrictors to the mother puts the child at risk for cardiovascular and neurological effects. Phenylephrine should not be used during lactation unless the potential benefit outweighs the potential risk. Fertility Kommentiert [VR18]: Modified according to Day 30 Comments from the CMS SI There are no data available regarding fertility after exposure to phenylephrine (see section 5.3).

Kommentiert [VR19]: Reply to Day 30 Comments from the CMS SE: modified to be in line with the most updated SmPC of the reference product Phenylephrine Injection BP 10 mg/ml’ (rev. date 4.7 Effects on ability to drive and use machines Nov. 2018) No adverse effects known. Kommentiert [VR20R19]: Modified according to Day 30 Comments from the CMS SE and to Day 48 Comments from the None stated. RMS. Biorphen 0.1 mg/ml has minor influence on the ability to drive and use machines. Kommentiert [VR21]: Applicant’s reply to NL comment VAR DE/H/4407/001-002/008: already modified, the following sentence was proposed in the frame of D60 reply of the RUP procedure

5 Page 6 Biorphen 0.1 mg/ml 1.3.1 Summary of Product Characteristics (SmPC)

Not relevant. Kommentiert [VR22]: Modified as per NL request

4.8 Undesirable effects Most of the adverse events of phenylephrine are dose-dependent and a consequence of the expected pharmacodynamic profile. The most common adverse events are bradycardia, hypertensive episodes, nausea and vomiting. Hypertension is more frequent with high doses. List of adverse reactions Frequency: not known (cannot be estimated from available data). System Organ Class Undesirable effect Immune system disorders Hypersensivity Metabolism and nutrition disorders Glucose metabolism abnormal Psychiatric disorders Euphoria, agitation, anxiety, psychotic states, confusion Nervous system disorders Headache, tingling, fullness head, nervousness, insomnia, paraesthesia, tremor Eye disorders , aggravation of pre-existing angle- closure glaucoma Cardiac disorders Reflex bradycardia, arrhythmia, tachycardia, cardiac arrest, anginal pain, palpitations, myocardial ischemia Vascular disorders Cerebral haemorrhage, hypertension, hypotension with dizziness, fainting, flushing, coldness of skin, pallor Respiratory, thoracic and mediastinal disorders Dyspnoea, pulmonary oedema Gastrointestinal disorders Vomiting, hypersalivation, nausea Skin and subcutaneous tissue disorders Diaphoresis, piloerection, sweating, skin blanching Renal and urinary disorders Difficulty in micturition, urinary retention General disorders and administration site Extravasation necrosis at injection site conditions

6 Page 7 Biorphen 0.1 mg/ml 1.3.1 Summary of Product Characteristics (SmPC)

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose Overdosage may induce ventricular extrasystole and short paroxysms of ventricular tachycardia, a sensation of fullness in the head and tingling of the extremities. Symptoms of overdosage include headache, vomiting, hypertension and reflex bradycardia and other cardiac arrhythmias. Should an excessive elevation of blood pressure occur, it may be immediately relieved by an a- blocking agent (e.g. , 5 to 60 mg i.v. over 10-30 minutes, repeated as necessary). Reflex bradycardia may be expected with a significant increase in blood pressure.

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5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Cardiac stimulants, excluding cardiac glycosides. Adrenergic and dopaminergic agents. ATC code: C01C A06 Kommentiert [VR23]: Modified according to Day 30 Comments from the CMS SI Mechanism of action Phenylephrine acts predominantly by a direct effect on alpha-adrenergic receptors. In therapeutic doses, the drug has no substantial stimulant effect on the beta-adrenergic receptors of the heart (beta1- adrenergic receptors) but substantial activation of these receptors may occur when larger doses are given. Phenylephrine does not stimulate beta-adrenergic receptors of the bronchi or peripheral blood vessels (beta2-adrenergic receptors). It is believed that alpha-adrenergic effects result from the inhibition of the production of cyclic adenosine-3',5'-monophosphate (cAMP) by inhibition of the enzyme adenyl cyclase, whereas beta-adrenergic effects result from stimulation of adenyl cyclase activity. Phenylephrine also has an indirect effect by releasing from its storage sites.

Pharmacodynamic effects The predominant actions of phenylephrine are on the cardiovascular system. Parenteral administration causes a rise in systolic and diastolic pressures. Accompanying the pressor response to phenylephrine is a marked reflex bradycardia that can be blocked by atropine; after atropine, large doses of the drug increase the heart rate only slightly. Cardiac output is slightly decreased and peripheral resistance is considerably increased. Circulation time is slightly prolonged, and venous pressure is slightly increased; venous constriction is not marked. Most vascular beds are constricted; renal splanchnic, cutaneous and limb blood flows are reduced but coronary blood flow is increased. Pulmonary vessels are constricted, and pulmonary arterial pressure is raised.

Clinical efficacy and safety Phenylephrine is a potent vasoconstrictor that acts almost exclusively through stimulation of alpha 1- adrenergic receptors. Such arterial vasoconstriction, also accompanied by venous vasoconstriction, provides an increase in blood pressure and bradycardia reflex and its pressor activity is weaker than that of noradrenaline but of longer duration. It is used parenterally in the treatment of hypotensive states, such as those encountered during circulatory failure, general or spinal anaesthesia or drug induced hypotension. In many published clinical studies phenylephrine was used in low-risk pregnant women undergoing spinal anesthesia during Cesarean delivery. Phenylephrine allowed to maintain maternal blood pressure near to baseline reduced the incidence of nausea and vomiting without causing foetal acidosis. Actually in therapeutic doses, it produces little if any stimulation of either the spinal cord or cerebrum. Kommentiert [VR24]: Deleted according to Day 30 Comments from the CMS SE A singular advantage of this drug is the fact that repeated injections produce comparable effects.

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The potent arterial vasoconstriction resulting in an increase in the resistance of ventricular ejection fraction (increased afterload). Which results in a reduction of cardiac output, this is less pronounced in healthy people but can be exacerbated in the case of previous heart failure.

5.2 Pharmacokinetic properties Distribution Kommentiert [VR25]: Modified according to Day 30 Comments from the CMS SI The volume of distribution after a single dose is 340 liters.

Elimination Phenylephrine is substantially excreted by the kidneys as m-hydroxymandelic acid and phenolic conjugates. When injected subcutaneously or intramuscularly, phenylephrine takes 10 to 15 minutes to act. Subcutaneous and intramuscular injections are effective for up to about one and up to two hours respectively. The duration is 20 minutes after intravenous administration. Plasma protein binding is unknown.

There are no data available on the pharmacokinetics in special populations.

5.3 Preclinical safety data There are no preclinical data of relevance to safety beyond that of the SmPC. There are no preclinical data on fertility and effects on reproduction after exposure of Biorphenphenylephrine. Kommentiert [VR26]: Modified according to Day 30 Comments from the CMS SI

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients Kommentiert [VR27]: Modified according to Day 30 Comments from the CMS SE and SI Sodium chloride, hydrochloric acid and (for pH adjustment) water for injections.

6.2 Incompatibilities Biorphen is not compatible with alkaline solutions, iron salts and other metals, phenytoin sodium and oxidising agents.

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This medicinal product must not be mixed with other medicinal products except those mentioned in Kommentiert [VR28]: Modified according to Day 30 Comments from the CMS SI section 6.6

6.3 Shelf life 3 years.

Use immediately after first opening. Kommentiert [PC29]: Modified according to Day 55 Comments from the CMS SI Kommentiert [VR30]: Modified according to Day 30 Comments from the CMS SI 6.4 Special precautions for storage Kommentiert [PC31]: Deletion proposed according to Day55 Comments of CMS SE and SI

Do not refrigerate or freeze. Kommentiert [VR32]: Applicant’s reply to RMS’s PVAR DE/H/4407/001-002/008: Modified accordingly , please refer to This medicinal product does not require any special storage conditions. Quality reply document

For storage conditions after first opening of the medicinal product, see section 6.3. Kommentiert [VR33]: Modified according to Day 30 Comments from the CMS SI Kommentiert [PC34]: Deletion proposed according to Day55 Comment of the SI for paragraph 6.3 6.5 Nature and contents of container Biorphen 0.1 mg/ml, solution for injection/infusion. Type I one point cut clear colourless glass 5 ml ampoules. Box of 10 ampoules containing 5 ml of solution for injection/infusion.

6.6 Special precautions for disposal and other handling The dilution before injection/infusion of Biorphen 0.1 mg/ml is not necessary. For single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER Sintetica GmbH Albersloher Weg 11 48155 Münster Germany

8. MARKETING AUTHORISATION NUMBER(S) To be completed nationally

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION To be completed nationally

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10. DATE OF REVISION OF THE TEXT To be completed nationally

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